Clinical trials dose-response relationship

Therapeutic confirmatory (Phase III) Demonstrate/confirm efficacy Establish safety profile Provide an adequate basis for assessing the benefit/risk relationship to support licensing Establish dose-response relationship Adequate and well controlled studies to establish efficacy Randomized parallel dose-response studies Clinical safety studies Studies of mortality/morbidity outcomes Large simple trials Comparative studies... 

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

For newer agents, defining the plasma level or dose-response relationship should be a priority to avoid using excessive doses for prolonged periods of time. This information may also be relevant for designing clinical trials using appropriate doses of neuroleptics for comparison trials against novel antipsychotics (i.e., parallel dose-response studies). 

Superiority, equivalence and noninferiority in clinical trials. The therapeutic efficacy of a novel drug is most convincingly established by demonstrating superiority to placebo, or to an active control treatment, or by demonstrating a dose-response relationship (as above). 

Emilien, G. van Meurs, W. Maloeaux, J.M. The dose-response relationship in Phase I clinical trials and beyond use, meaning, and assessment. Pharmacol. Ther. 2000, 88 (1), 33-58. 

Although a dose-response relationship for inhaled corticosteroids has not been demonstrated in COPD, the major clinical trials employed moderate to high doses for treatment. Side effects of inhaled corticosteroids are relatively mild compared with the toxicity from systemic therapy. Hoarseness, sore throat, oral candidiasis, and skin bruising have been reported in the clinical trials. Severe side effects, such as adrenal suppression, osteoporosis, and cataract formation, have been reported less frequently than with systemic corticosteroids, but clinicians should monitor patients who are receiving high-dose chronic therapy. ... 

The Merriam Webster s Collegiate Dictionary defines toxicology as a science that deals with poisons and their effect and with the problems involved (as clinical, industrial, or legal). The science of toxicology has been instrumental in developing the animal and early human trials to develop new pharmaceuticals. The dose-response relationship is the defining principle of this science. 

Phase II clinical trials are designed to evaluate the producfs efficacy and side-effect profile. About 100-300 patients are involved. Data obtained are used to characterize the dose-response relationship. The costs involved are about 10-100 million Euro over 1- to 2-year period. The success rate is about 40%. Studies performed may be characterized by a single or multicenter study, single- or double-blinded with a control group and randomization of the patients. Amongst the most common reasons for failure at this phase are poorly designed studies and ineffective or unsafe products. 

Tangen CM, Koch GG (2001) Non-parametric analysis of covariance for confirmatory randomized clinical trials to evaluate dose - response relationships. Statistics in Medicine 20 2585-2607. 

Knowledge regarding whether an AE of interest exhibits a potential dose-response relationship is important in the overall assessment of a compound. In order to thoroughly evaluate whether an AE rate increases with increasing dose level, evidence from multiple clinical trials needs to be combined and analyzed, often with differing dose levels. 

From an analysis standpoint, often only the trials with all common doses are included, which can exclude important information. One may also crudely pool patients at the same dose level across studies, but the drawback is that it breaks down the randomization. Bayesian methodology has been shown to be useful in the context of indirect and mixed treatment comparison methods, to combine information from different therapies in different studies in order to make treatment effect inferences, but instead of modeling differenf dose arms in different studies, we extend the methodology to allow for assessment of the dose-response relationship across multiple clinical trials. 

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